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Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.

Publication ,  Journal Article
Mallaredy, V; Roy, R; Cheng, Z; Thej, C; Benedict, C; Truongcao, M; Joladarashi, D; Magadum, A; Ibetti, J; Cimini, M; Gonzalez, C; Koch, WJ ...
Published in: Circ Res
July 5, 2024

BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.

Duke Scholars

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

July 5, 2024

Volume

135

Issue

2

Start / End Page

280 / 297

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Up-Regulation
  • Random Allocation
  • Quinolones
  • Myofibroblasts
  • Myocytes, Cardiac
  • MicroRNAs
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Mallaredy, V., Roy, R., Cheng, Z., Thej, C., Benedict, C., Truongcao, M., … Kishore, R. (2024). Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure. Circ Res, 135(2), 280–297. https://doi.org/10.1161/CIRCRESAHA.123.324110
Mallaredy, Vandana, Rajika Roy, Zhongjian Cheng, Charan Thej, Cindy Benedict, May Truongcao, Darukeshwara Joladarashi, et al. “Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.Circ Res 135, no. 2 (July 5, 2024): 280–97. https://doi.org/10.1161/CIRCRESAHA.123.324110.
Mallaredy V, Roy R, Cheng Z, Thej C, Benedict C, Truongcao M, et al. Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure. Circ Res. 2024 Jul 5;135(2):280–97.
Mallaredy, Vandana, et al. “Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.Circ Res, vol. 135, no. 2, July 2024, pp. 280–97. Pubmed, doi:10.1161/CIRCRESAHA.123.324110.
Mallaredy V, Roy R, Cheng Z, Thej C, Benedict C, Truongcao M, Joladarashi D, Magadum A, Ibetti J, Cimini M, Gonzalez C, Garikipati VNS, Koch WJ, Kishore R. Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure. Circ Res. 2024 Jul 5;135(2):280–297.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

July 5, 2024

Volume

135

Issue

2

Start / End Page

280 / 297

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Up-Regulation
  • Random Allocation
  • Quinolones
  • Myofibroblasts
  • Myocytes, Cardiac
  • MicroRNAs
  • Mice, Inbred C57BL
  • Mice
  • Male